The long-term goal of this project is to shed light on the nature of the hematopoietic cell defects in paroxysmal nocturnal hemoglobinuria )PNH). A corollary goal is to assess the effects of the cell defects on total body function, via the effects of intravascular hemolysis and of the remarkable thrombotic tendency in PNH on organ structure and function. At a clinical level studies will be extended on the inherent iron deficiency in PNH to replete body Fe without precipitating gross hemoglobinuria with use of very low dose oral Fe. Studies will also be furthered on bone and renal disease secondary to chronic thrombosis in the micro-circulation. The major thrust will concern an extended study of hepatic venous thrombosis (Budd-Chiari syndrome) (BCS) as a frequent, highly lethal complication of PNH. We have defined the onset of fulminant hepatic venous thrombosis (HVT) in PHN as a medical emergency as well as the means of prompt clinical diagnosis and early, aggressive and prolonged heparinization followed by coumadin, all aimed at reversing the high mortality rate. Additionally liver scan survey has unearthed a smoldering case of HVT in PNH, now on coumadin. Work has begun on creating an animal model for HVT, relying principally on prolonged, daily intraperitoneal injections of isologous hemolysed blood. We have shown that the diagnostic sucrose hemolysis test leaves complement (C) components on residual, unlysed PNH RBC which can then be lysed by restoration of isotonicity. The nature of these C components will be investigated. RBC membrane protease was found to be low in a significant portion of PNH patients but not in all. Those PNH patients with normal RBC protease activity had some features different from the group with low enzyme activity, but complete explanation for the difference is not currently established. Studies will be continued to assess RBC protease in PNH and related disorders.